Modified release pharmaceutical dosage forms have long been used to optimize drug delivery and enhance patient compliance, especially by reducing the number of doses of medicine the patient must take in a day. In some instances, it is also desirable for a dosage form to deliver more than one drug at different rates or times. Modified release dosage forms should ideally be adaptable so that release rates and profiles can be matched to physiological requirements. Because the onset and duration of the therapeutic efficacy of drugs vary widely, as do their absorption, distribution, metabolism, and elimination, it is often desirable to modify the release of different drugs in different ways, or to have a first dose of drug immediately released from the dosage form, while a second dose of the same or a different drug is released in a modified, e.g., delayed, pulsatile, repeat action, controlled, pH dependent, sustained, prolonged, extended, or retarded manner.
Well known mechanisms by which a dosage form can deliver drug at a controlled rate include permeation, diffusion, erosion, and osmosis. It is often practical to design dosage forms that use a combination of the above mechanisms to achieve a particularly desirable release profile for a particular active ingredient.
An important objective of modified release dosage forms is to provide a desired blood concentration versus time (pharmacokinetic, or PK) profile for the drug. Fundamentally, the PK profile for a drug is dependent on the rate of absorption of the drug into the blood, and the rate of elimination of the drug from the blood. To be absorbed into the blood (circulatory system), the drug must first be dissolved in the gastrointestinal fluids. For those relatively rapidly absorbed drugs whose dissolution in the gastrointestinal fluids is the rate limiting step in drug absorption, controlling the rate of dissolution (i.e., drug release from the dosage form) allows the formulator to control the rate of drug absorption into the circulatory system of a patient. The type of PK profile, and correspondingly, the type of dissolution or release profile desired, depends on, among other factors, the particular active ingredient and physiological condition being treated.
One particularly desirable PK profile is achieved by a dosage form that delivers a delayed release dissolution profile, in which the release of one or more doses of drug from the dosage form is delayed for a pre-determined time after contacting of the dosage form by a liquid medium, such as for example, by the gastro-intestinal fluid after ingestion by the patient. The delay period (“lag time”) can be followed either by prompt release of the active ingredient (“delayed burst”), or by sustained (prolonged, extended, or retarded) release of the active ingredient (“delayed then sustained”). U.S. Pat. No. 5,464,633 to Jagotec, for example, discloses delayed-release dosage forms consisting of a core containing an active and polymeric substances and an external layer completely coating the core in which the external coating layer is applied by a compression coating process.
One particularly desirable type of delayed release PK profile is obtained from a “pulsatile” release profile, in which for example, a first dose of a drug is delivered, followed by a delay period (“lag time”) during which there is substantially no release of the drug from the dosage form, followed by either prompt or sustained release of a subsequent dose of the same drug. In one particularly desirable type of pulsatile drug delivery system, the first dose is released essentially immediately upon contacting of the dosage form with a liquid medium and the delay period corresponds approximately to the time during which a therapeutic concentration of the first dose is maintained in the blood. Pulsatile delivery systems are particularly useful for applications where a continuous release of drug is not ideal. Examples of this are drugs exhibiting first pass metabolism by the liver, drugs that induce biological tolerance, i.e., the therapeutic effect decreases with continuous presence of the drug at the site of action, and drugs whose efficacy is influenced by circadian rhythms of body functions or disease. One typical pulsatile dosage form design contains the first dose of drug in an exterior coating, or shell, while subsequent doses of drug are contained in underlying layers of subcoatings, or a central core. Pulsatile dosage forms may deliver an active ingredient in a pH dependent or pH independent manner. pH dependent types of dosage forms typically deliver the active ingredient through the addition of a pH dependent polymer, such as an enteric or reverse-enteric polymer.
PCT Publication No. WO99/62496 to Alza, for example, discloses a dosage form comprising an immediate-release dose of drug contained within an overcoat applied onto a surface of a semi-permeable coating of an osmotic dosage form. U.S. Pat. Nos. 4,857,330 and 4,801,461 to Alza disclose dosage forms comprising an exterior drug coat that surrounds a semi-permeable wall, which in turn surrounds an internal compartment containing a second dose of drug, and comprises exit means for connecting the interior of the dosage form with the exterior environment of use. These dosage forms are designed to release drug immediately from the exterior coating, followed by a relatively short delay period, followed by a sustained release of drug from the internal compartment.
U.S. Pat. No. 4,865,849 to Pharmidea discloses a tablet that releases active substances at successive times, comprising a first layer containing a portion of the active substance, a water soluble or water gellable barrier layer, and a third layer containing the remaining portion of active substance, wherein the barrier layer and the third layer are in an insoluble, low-permeable casing. The casing can be applied by various methods such as spraying, compression, or immersion, or the tablet parts can be inserted into a pre-formed casing. These systems suffer from the complexity and high cost of assembling multiple, separate compartments comprising multiple, different compositions.
U.S. Pat. No. 4,839,177 to Jagotec, discloses a system for the controlled release of active substances, consisting of: (a) a deposit-core; and (b) a support-platform applied to the deposit-core. The deposit-core contains active substance and a polymeric material having a high degree of swelling on contact with water or aqueous liquids, a gellable polymeric material, and other adjuvants able to provide the mixture with suitable characteristics for its compression and for its intake of water.
U.S. Pat. No. 6,126,767 to Perrigo, discloses a capsule medicament consisting of a solid core covered with two shrink-wrapped, hard-shell gelatin capsule halves. The solid core is covered with the hard-shell gelatin capsule halves by individually shrink-wrapping onto first one end of the core a first hard-shell gelatin capsule half and then individually shrink-wrapping onto a second end of the core a second hard-shell gelatin capsule half. The capsule medicament is designed for immediate release of the active ingredient.
U.S. Pat. No. 6,113,945 to Perrigo, discloses a caplet or tablet core with a clear or single color uniform covering that is applied either through an enrobing process, by spraying or by a single dip-coating step. The core itself can have a first color or be colorless, and its clear or single color covering has the outer surface of one end or one side colored by a dye to provide a two-color appearance. The dye can be applied by dipping or spray painting with a jet-spraying apparatus.
U.S. Pat. No. 6,787,156 to BM Research discloses a composition for controlled delivery of at least one active substance comprising a first cellulose derivative which has thermoplastic properties and which is substantially insoluble in an aqueous medium in which the composition is to be used, and at least one of a second cellulose derivative which is soluble or dispersible in water, a plasticizer, and a filler.
U.S. Patent Publication No. 20030070584 to McNeil discloses a water soluble, gelatin-free dip coating for pharmaceutical solid dosage forms such as tablets comprising HPMC and xanthan gum, carrageenan, and mixtures thereof, or HPMC and castor oil or maltodextrin.
U.S. Patent No. 20080166407 to Shalaby et al. discloses multifunctional, single, bilayer, and trilayer coated tablets for combination therapy wherein the bioactive agents responsible for the therapeutic multifunctionality are present as a combination of a gastric acid-reducing agent, such as omeprazole and ranitidine, and at least one analgesic/anti-inflammatory agent, such as acetaminophen, naproxen sodium, ibuprofen, tolmetin, and aspirin.
All references cited are incorporated by reference in their entirety herein.
Coating methods such as those described above have inherent disadvantages, including long processing times, limited ability to allow functional placement of coatings, or multiple coating steps in order to provide multiple release rates (as in spray coatings), thick coatings which can affect swallowability and limit types of release rates (such as compression coatings), or the use of laser drilling equipment (such as osmotic coatings).
There is a need in the art for improved dosage forms for providing modified release of active ingredient.